Oral treatment of rodents with soluble epoxide hydrolase inhibitor 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU): Resulting drug levels and modulation of oxylipin pattern

Depression is a severe and chronic psychiatric disease, affecting 350 million subjects worldwide. Although multiple antidepressants have been used in the treatment of depressive symptoms, their beneficial effects are limited. The soluble epoxide hydrolase (sEH) plays a key role in the inflammation that is involved in depression. Thus, we examined here the role of sEH in depression. In both inflammation and social defeat stress models of depression, a potent sEH inhibitor, TPPU, displayed rapid antidepressant effects. Expression of sEH protein in the brain from chronically stressed (susceptible) mice was higher than of control mice. Furthermore, expression of sEH protein in postmortem brain samples of patients with psychiatric diseases, including depression, bipolar disorder, and schizophrenia, was higher than controls. This finding suggests that increased sEH levels might be involved in the pathogenesis of certain psychiatric diseases. In support of this hypothesis, pretreatment with TPPU prevented the onset of depression-like behaviors after inflammation or repeated social defeat stress. Moreover, sEH KO mice did not show depressionlike behavior after repeated social defeat stress, suggesting stress resilience. The sEH KO mice showed increased brain-derived neurotrophic factor (BDNF) and phosphorylation of its receptor TrkB in the prefrontal cortex, hippocampus, but not nucleus accumbens, suggesting that increased BDNF-TrkB signaling in the prefrontal cortex and hippocampus confer stress resilience. All of these findings suggest that sEH plays a key role in the pathophysiology of depression, and that epoxy fatty acids, their mimics, as well as sEH inhibitors could be potential therapeutic or prophylactic drugs for depression.brain-derived neurotrophic factor | depression | epoxyeicosatrienoic acid | soluble epoxide hydrolase | resilience

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“…S2 A and B). The pharmacokinetic data suggest that TPPU can enter into the brain, consistent with a recent report (35).…”

Section: Significancesupporting

confidence: 90%

Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress

Ren

Ishima

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Previously, reductions in plasma DiHOME levels and increased plasma EpOME/DiHOME ratios were observed after oral TPPU treatment of rodents, which demonstrated target engagement and sEH inhibition. 32 In this study, plasma levels of total DiHOMEs were reduced, and the reduction was statistically significant versus controls in the TPPU + EET group (Fig. 4B).…”

Section: Resultssupporting

confidence: 53%

“…Efficient inhibition of sEH is predicted to reduce diol levels and increase the epoxide/diol ratio, although relative levels may vary in different tissues. 32 No significant differences were observed in plasma DiHETEs; however, significantly higher levels were detected in tissue biopsies of mice treated with TPPU + EET compared with TPPU-treated mice and controls (See figure, Supplemental Digital Content 4 , http://links.lww.com/PRSGO/A331). This can likely be attributed to breakdown of topically applied exogenous EETs in this group.…”

Section: Resultsmentioning

confidence: 99%

Soluble Epoxide Hydrolase Inhibition and Epoxyeicosatrienoic Acid Treatment Improve Vascularization of Engineered Skin Substitutes

Supp

Hahn

McFarland

et al. 2016

Plastic and Reconstructive Surgery - Global Open

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“…A study showing the blood levels of TPPU given at a range of concentrations has been published [27]. Continuous exposure to TPPU results in steady state levels [31]. All groups gained weight during the experiment, with the ω-3 only group gaining the most (Supplementary Materials Figure S7).…”

Section: Resultsmentioning

confidence: 99%

An ω-3-enriched diet alone does not attenuate CCl 4 -induced hepatic fibrosis

Harris

Kodani

Yang

et al. 2016

The Journal of Nutritional Biochemistry

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Exposure to the halogenated hydrocarbon carbon tetrachloride (CCl4) leads to hepatic lipid peroxidation, inflammation, and fibrosis. Dietary supplementation of ω-3 fatty acids has been increasingly advocated as being generally anti-inflammatory, though its effect in models of liver fibrosis is mixed. This raises the question of whether diets high in ω-3 fatty acids will result in a greater sensitivity or resistance to liver fibrosis as a result of environmental toxicants like CCl4. In this study we fed CCl4-treated mice a high ω-3 diet (using a mix of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) ethyl esters). We also co-administered an inhibitor of soluble epoxide hydrolase, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), which has been shown to boost anti-inflammatory epoxy fatty acids that are produced from both ω-3 and ω-6 dietary lipids. In this study, we showed that soluble epoxide inhibitors reduced CCl4-induced liver fibrosis. Three major results were obtained. First, the ω-3 enriched diet did not attenuate CCl4-induced liver fibrosis as judged by collagen deposition and collagen mRNA expression. Second, the ω-3 enriched diet raised hepatic tissue levels of several inflammatory lipoxygenase metabolites and prostaglandins, including PGE2. Third, treatment with TPPU in drinking water in conjunction with the ω-3 enriched diet resulted in a reduction in liver fibrosis compared to all other groups. Taken together, these results indicate that dietary ω-3 supplementation alone did not attenuate CCl4-induced liver fibrosis. Additionally, oxylipin signaling molecules may play role in the CCl4-induced liver fibrosis in the high ω-3 diet groups.

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Oral treatment of rodents with soluble epoxide hydrolase inhibitor 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU): Resulting drug levels and modulation of oxylipin pattern

Cited by 43 publications

References 42 publications

Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress

Gene deficiency and pharmacological inhibition of soluble epoxide hydrolase confers resilience to repeated social defeat stress

Soluble Epoxide Hydrolase Inhibition and Epoxyeicosatrienoic Acid Treatment Improve Vascularization of Engineered Skin Substitutes

An ω-3-enriched diet alone does not attenuate CCl 4 -induced hepatic fibrosis

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